Evidence accumulated over the past decade has strengthened the case for T cell-mediated mechanisms of protection against HIV, including cytotoxic T lymphocytes (CTLs) and chemokine-secreting T cells. A major impediment to the development of an HIV-1 vaccine that elicits such immunity, however, has been the lack of a T cell-mediated response that correlates with protection. For example, there is no definitive evidence correlating CTL responses with protection against SIV or HIV. On the other hand, recent evidence showing that chemokine-secreting T cells can suppress HIV-1 infection in vitro, suggest a new mechanism of T cell-mediated protection. Clearly, these studies justify continued investigation of the means by which T cell-mediated responses can be induced by HIV-1 vaccines. In this vein, the central hypothesis of this proposal is that a live oral Salmonella-HIV-1 vaccine vector will induce such responses in the mucosal and systemic compartments. In the preliminary data section we present immunological data that strengthen our central hypothesis and demonstrate the importance of HIV-1 antigen placement. Thus, we showed that a single oral dose of a Salmonella-HIV vector, bearing a secreted form of non-glcosylated gp120, induced gp120-specific T cells that were predominated by IFN-gamma- secreting CD4+ T cells and a strong gp120-specific mucosal response. Furthermore, our data suggest that beta chemokine-secreting CD4+ and to a lesser extent CD8+ T cells develop during the inductive events after oral immunization with live Salmonella. Finally, we have shown that human-specific attenuated Salmonella strain CVD908 is well tolerated and immunogenic in volunteers. We now propose to extend these findings by further exploring the relationship between HIV antigen placement within the vector or within the host and the magnitude and phenotype of the HIV-specific cellular responses in mucosal and systemic sites that develop after immunization with out Salmonella vectors. We believe that this approach will provide fundamental information germane to the development of an oral Salmonella-HIV-1 vaccine.